Gluten intolerance is found predominantly in areas where wheat is a major food source, (e.g., Europe, North America and Australia). In these areas, the incidence of the disease is about 1 per 100 head of population (DA Van Heel et al, Gut 2006; 55:1037-1046). The symptoms of this condition include abdominal pain, bloating and diarrhoea. In severe and long term cases, such as in coeliac disease, there are inflammatory changes to the intestinal mucosa, resulting in malabsorption of nutrients, fatigue, chronic diarrhoea, weight loss, abdominal distension, anaemia, increased tendency to haemorrhage, as well as increased risk of gastrointestinal malignancies, such as lymphoma and carcinoma.
The pathogenesis of gluten intolerance (or coeliac disease, coeliac sprue) appears to have both genetic and environmental factors. Whilst genetic predisposition is a major factor (about 10% of first degree relatives are affected), the fact that monozygotic twins have a concordance rate of only about 75% suggests that environment also plays a part in the development of the disease.
Patients with gluten intolerance characteristically have T cells present in the intestinal mucosa which recognize certain sequences present in toxic gluten peptides. Evidence suggests that these T cells play a crucial role in the immunopathogenesis of the disease by recognising peptides containing specific sequences of amino acids associated with toxicity. For instance, the proliferation of gliadin-specific HLA-DQ2-restricted T cell clones from the intestine of coeliac disease patients can be initiated in vitro by the addition of a water-soluble, partially digested form of gliadin to HLA-DQ2 carrying antigen-presenting cells.
A related disease associated with severe gluten intolerance is dermatitis herpetiformis, which presents as a chronic eruption characterized by clusters of intensely pruritic vesicles, papules, and urticaria-like lesions. Studies have shown that IgA deposits occur in almost all normal-appearing and perilesional skin. Asymptomatic gluten-sensitive enteropathy is found in 75 to 90% of patients and in some of their relatives. The onset of dermatitis herpetiformis is usually gradual, progressing to severe itching and burning of the affected surface. Moreover, scratching often obscures the primary lesions with eczematization of nearby skin, leading to an erroneous diagnosis of eczema.
Gluten is a protein fraction found, for example, in cereal dough, which can be subdivided into glutenins and prolamins. Prolamins may also be subclassified as gliadins, secalins, hordeins, and avenins from wheat, rye, barley and oat, respectively. Among gluten proteins with potential harmful effect to gluten intolerant patients are the storage proteins of wheat, species of which include Triticum aestivum; Triticum aethiopicum; Triticum baeoticum; Triticum militinae; Triticum monococcum; Triticum sinskajae; Triticum timopheevii; Triticum turgidum; Triticum urartu, Triticum vavilovii; Triticum zhukovskyi; etc. (see, for example, Colot, Genet Eng (NY) 12:225-41, 1990).
Gliadin is the 70% alcohol-soluble protein fraction of wheat gluten. Derived from wheat flour, gliadins can be classified into several groups according to their electrophoretic mobility, including α-type, β-type, γ-type and ω-type. Gliadins are typically rich in glutamine and proline, particularly in the N-terminal part. For example, the first 100 amino acids of α and γ-gliadins contain about 35% and about 20% of glutamine and proline residues, respectively. Different gliadins are present in each subcultivar of wheat, with variations in the amino acid sequences within each type. Gliadins are typically characterized by a molecular mass of around 30-50 kDalton and their insolubility in neutral aqueous solutions. Examples of gliadin sequences include but are not limited to wheat α-gliadin sequences, for example as provided in Genbank, accession numbers AJ133612; AJ133611; AJ133610; AJ133609; AJ133608; AJ133607; AJ133606; AJ133605; AJ133604; AJ133603; AJ133602; D84341.1; U51307; U51306; U51304; U51303; U50984; and U08287. A sequence of wheat omega gliadin is set forth in Genbank accession number AF280605.
It has been discovered that in gluten intolerant individuals, enzymes normally present in the small bowel that are necessary for the digestion of gluten are missing. Peptide fragments produced by incomplete digestion of grain protein are toxic to such individuals; the most toxic peptides being those derived from α-gliadin, or a similar protein called A-gliadin.
Serine-containing peptides, (containing PSQQ and possibly also QQQP motifs, as found in residues 11-19 of A-gliadin), appear to have a cytotoxic effect. Tyrosine-containing peptides, (containing QQPY and/or QPYP motifs, as found in residues 75-86 of A-gliadin), are associated with immunological activity through T-cell mediation and hence, toxicity.
Experiments indicate that active serine-containing peptides like 11-19 and active tyrosine-containing peptides like 75-86 are incompletely digested by mucosal enzymes in patients suffering from coeliac disease. The residual peptide sequences, such as 11-18 and 77-84, are still toxic, which suggests that the aetiology of coeliac disease is connected to defective mucosal digestion and that the pathogenesis of the disease results from the action of the undigested peptides on the mucosa. This may ultimately be due to deficiency in a single enzyme in coeliac disease patients, but at least two different types of peptide residues build up and cause damage to mucosal tissue.
At present, there is no effective therapy for treating the effects of gluten intolerance other than to impose a gluten-free diet on the patient. However, due to the number of food products containing either cereals comprising gluten, or gluten per se, this approach constitutes a severe restriction to the food choices available to a patient. Moreover, although gluten withdrawal has improved the prognosis of gluten intolerant patients, some people still die of the disease, presumably from lymphoreticular disease (especially intestinal lymphoma), particularly in those people who present with severe gluten intolerance at the outset. It appears that gluten withdrawal diminishes the risk of developing lymphoreticular disease, whilst apparent clinical remission is often associated with histologic relapse that is detected only by review biopsies or by an increased IgA class anti-endomysial antibody (EMA) titre.
In view of the serious and widespread nature of gluten intolerance, improved methods of treating, preventing or ameliorating the effects of this condition are needed. Accordingly, it is an aspect of the present invention to overcome, or at least partly alleviate, some of the aforementioned problems of the art by providing improved compositions for preventing or treating conditions arising from gluten intolerance and methods for their use.
The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.